I. Field of the Invention
The present invention relates a process for producing 1-(2'-deoxy-.beta.-D-erythro-pentofuranosyl)-5-trifluoromethyluracil derivatives having anti-tumor and anti-viral activities, as well as to a process for producing an intermediate thereof.
II. Description of the Related Art
1-(2'-deoxy-.beta.-D-erythro-pentofuranosyl)-5-trifluoromethyluracil derivatives (trifluorothymidine derivatives) are compounds which have long been drawing attention because of their relationships between uridine or thymidine. Since they have anti-tumor and anti-viral activities, they are important as pharmaceuticals or intermediates for producing the pharmaceuticals, so that processes for producing them have been well studied. It is well known in the field of synthetic organic chemistry in this area that the processes for producing the derivatives largely vary depending on the type of the base in the nucleoside, so that a suitable production process should be studied for each type of the bases. For example, as described in Nucleic Acids Research 12, 6827 (1984) or in Nucleosides & Nucleotides, 8, 549 (1989), bases of nucleic acids, such as uracil, fluorouracil, thymine and trifluorothymine have largely different properties because of the difference in the substituent group on 5-position. Therefore, a production process by utilizing glycosylation must be developed for each of the above-mentioned bases. Especially, 5-trifluoromethyluridine has chemical properties largely different from those of uridine and thymidine because of the influence by the trifluoromethyl group, so that 5-trifluoromethyluridine cannot be produced well by a production process analogous to the process for producing uridine or thymidine. Further, if a compound having 2'-deoxy structure in the sugar moiety is produced by a conventional process, the selectivity of .alpha. and .beta. isomers is low, so that it is difficult to selectively obtain the necessary .beta. isomer alone.
Known processes for producing 1-(2'-deoxy-.beta.-D-erythro-pentofuranosyl)-5-trifluoromethyluracil derivatives include:
(1) A process in which the base of thymidine is exchanged with 5-trifluoromethyluracil by nucleoside-2'-deoxyribose transferase or the like (M. G. Stout et al., Methods Carbhydro Res., 7, 19 (1976); PA1 (2) A process in which the halogen atom at 5-position of a 1-(2'-deoxy-.beta.-D-erythro-pentofuranosyl)-5-halouracil derivative is reacted with trifluoromethylcopper (Y. Kobayashi, et al., J. C. S. Perkin Trans I, 2755 (1980)); PA1 (3) A process in which a thymidine derivative and trifluoroacetic acid are subjected to electrolysis reaction (L. Hein, et al., DE 119423 (1976)); PA1 (4) A process in which 5-trifluoromethyl-2,4-bistrimethylsilyloxy)pyrimidine and methyl 2-deoxy-D-erhythro-pentofuranoside derivative are reacted in the presence of an acid catalyst (Japanese Laid-open PCT Application (Kohyo) No. 62-500239)); and PA1 (5) A process in which 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine and 3,5-di-O-(p-chlorobenzoyl)-2-deoxy-.alpha.-D-erythro-pentofuranosyl chloride are reacted in the presence of zinc chloride catalyst (Japanese Laid-open Patent Application (Kokai) No. 2-289595, Heterocycles, 31, 569 (1990)). PA1 (1) A process in which 5-hydroxycarbonyluracil is reacted with SF.sub.4 (M. P. Merite, et al., J. Pharm. Sci., 2, 508 (1963)); PA1 (2) A process in which 5-iodouracil is reacted with trifluoromethylcopper (Y. Kobayashi et al., J. C. S. Perkin I, 2755 (1980)); PA1 (3) A process in which uracil and trifluoroacetic acid are subjected to electrolysis reaction (L. Hein, D. Cech, Z. Chem., 17,415 (1977)); PA1 (4) A process in which 5-trifluoromethyl-5,6-dihydrouracil is reacted with bromine (C. Heiderberger, et al., J. Med. Chem., 7, 1 (1964); Japanese Laid-open Patent Application (Kokai) No. 58-174371); and PA1 (5) A process in which 5-trifluoromethyl-5,6-dihydrouracil is reacted with cupric halide (Japanese Laid-open Patent Application (Kokai) No. 60-94971). PA1 (b) reacting the obtained 5-trifluoromethyluracil with a silylating agent to obtain 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine of the formula (1) ##STR3## and (c) reacting the obtained 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine with 2-deoxy-.alpha.-D-erythro-pentofuranosyl halide derivative of the formula (2) ##STR4## (wherein X represents a halogen atom, preferably chlorine atom, preferably chlorine atom, and X.sup.1 and X.sup.2, the same or different, represent hydrogen or a halogen atom, preferably hydrogen or chlorine atom) in chloroform solvent in the presence of fluoride ion and in the presence of a copper compound as a catalyst.
However, the above-mentioned process (1) has a drawback in that isolation of the desired product from the reaction system is difficult so that it is difficult to produce the desired product in a large scale. The process (2) has a drawback in that a reaction intermediate is very sensitive to air, so that it is difficult to set reaction conditions and the yield is low. The process (3) has a drawback in that both the yield and electric efficiency are low, and an equipment for electrolysis which can withstand trifluoroacetic acid is necessary. The process (4) has a drawback in that the desired product is obtained as a racemate which is difficult to resolve, so that isolation yield of the desired .beta. isomer is very low. The process (5) has a drawback in that expensive 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine is required in a large amount. Further, in this process, it is necessary to employ zinc chloride which is hygroscopic and insoluble in solvents, and so has poor ease of handling as a catalyst, so that the reproducibility of the process is low and it is difficult to carry out the process in an industrial scale. Still further, if the expensive 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine is used in an amount smaller than the equimolar amount, the selectivity to .beta. isomer is extremely decreased, so that the yield of the desired .beta. isomer is largely reduced.
Thus, none of the conventional processes is suited as a process for producing 1-(2'-deoxy-.beta.-D-erythropentofuranosyl)-5-trifluoromethyluracil derivatives which are important as pharmaceuticals or intermediates thereof in a large scale at a low cost with certainty. Thus, an improved process for producing 1-(2'-deoxy-.beta.-D-erythropentofuranosyl)-5-trifluoromethyluracil derivatives is demanded.
On the other hand, trifluoromethyluracil is a compound which has been drawing attention because of the relationship between uracil or thymine that is a base of nucleic acid. Especially, processes for producing triflurothymidine derivatives which are used as anti-cancer agents or anti-viral agents because of their specific physical properties and actions, or as important intermediates for the production of pharmaceuticals such as 1-(2'-deoxy-.beta.-D-erythro-pentofuranosyl)-5-trifluoromethyluracil derivatives, have been intensively studied. Conventional processes for producing 5-trifluoromethyluracil include:
However, the above-mentioned process (1) has a drawback in that dangerous SF.sub.4 having high toxicity must be used. The process (2) has a drawback in that a reaction intermediate is very sensitive to air, so that it is difficult to set reaction conditions and the yield is low. The process (3) has a drawback in that both the yield and electric efficiency are low, and an equipment for electrolysis, which can withstand trifluoroacetic acid is necessary. The process (4) has a drawback in that more than twice the stoichiometric amount of bromine is required and the yield is low. The process (5) has a drawback in that a large amount of residue containing copper salt is generated after the reaction, so that there are problems in ease of operation and disposal of the copper salt-containing residue.
Thus, none of the conventional processes for producing trifluoromethyluracil is a process by which the desired product is produced at a low cost with certainty. Thus, an improved process is demanded.